Chapter 16 – Electrophilic Nitro-Fatty Acids: Nitric Oxide and Nitrite-Derived Metabolic and Inflammatory Signaling Mediators

Abstract The modification of cell proteins by metabolically and environmentally induced redox reactions significantly expands the functional proteome. These posttranslational modifications (PTMs) of proteins allow cells to dynamically regulate metabolism, growth, differentiation, and immune responses. In particular, PTMs continue to emerge as a critical component of nitric oxide (NO) and “redox” signaling. In addition to its role in activating guanylate cyclase via heme-iron coordination, NO reacts with superoxide and lipid radicals and is further oxidized by metalloproteins to yield some of the most reactive molecules in biology. These reactions yield secondary nitrogen oxides, such as nitrogen dioxide, that expand the breadth of reactions transducing redox-dependent signaling responses. One class of by-products, unsaturated fatty acid nitroalkene derivatives (nitro-fatty acids), is electrophilic and induces PTMs by reversible Michael addition of protein thiols. Since multiple transcriptional regulatory mechanisms have protein constituents with functionally significant electrophile-reactive amino acids, this represents a population of nitro-fatty acid–responsive protein targets. This highly conserved property provides cells with a capability to undergo stress-related adaptive gene expression and signaling reactions, in response to increased levels of lipid electrophile generation. This chapter reviews model system and clinical data regarding the mechanisms of formation of electrophilic nitro-fatty acid derivatives and their antiinflammatory actions in model systems and FDA-approved clinical trials. The molecular targets, shifts in gene transcription patterns, cell signaling reactions, and physiological responses induced by low concentrations of electrophilic nitro-fatty acids reveal that these mediators are nontoxic and mediate antiinflammatory and adaptive signaling responses.